Reinforcement-enhancing effects of nicotine Nicotine clearly has primary and secondary reinforcing effects in humans and animal models. Very recent research in rodents indicates that nicotine may also have a third reinforcing function; that of reinforcement-enhancing effects, or increasing the reinforcing efficacy of rewards unrelated to nicotine intake. This R21 application seeks to determine whether nicotine via smoking has reinforcement enhancing effects in humans. One hundred smokers, 50 nicotine dependent and 50 nondependent, will participate in 4 experimental sessions, involving: 1) smoking nicotine (0.6 mg) cigarettes or 2) smoking denic (0.05 mg) cigarettes or 3) no smoking, each after overnight abstinence, or 4) smoking their own brand after no overnight abstinence (exploratory condition). In each session, they will respond on a simple operant task for small amounts of money, brief access to preferred music, avoidance of aversive white noise, or no reward (control). Our primary specific aim is to examine the influence of nicotine via smoking on responding for rewards. We hypothesize that reinforced responding will be greater after smoking a nicotine vs a denic cigarette (and vs. no smoking), indicating reinforcement enhancing effects of nicotine per se. Effects of nicotine on responding for some rewards versus others or no reward will indicate that reinforcement enhancement due to nicotine is specific to certain rewards and not a generalized effect of nicotine intake. Reinforcement-enhancing effects of nicotine in nondependent smokers, as well as dependent smokers, would suggest that these effects do not require the establishment of dependence and reflect absolute enhancement of reinforcement, as observed in the rodent studies. Substantial pilot work supports project feasibility and points to the likelihood of these hypothesized results. By contrast, if effects are observed only in dependent and not nondependent smokers, they could reflect withdrawal relief and not true enhancement of reinforcement. A secondary aim is to explore sex differences in the reinforcement enhancing effects of nicotine. This research is highly significant because demonstrating reinforcement-enhancing effects of nicotine in humans would have very important implications for our understanding of nicotine dependence. It would indicate that smoking does not just provide reinforcement from direct psychoactive effects of nicotine but rather broadly increases the reinforcing effects of the other rewards in a smoker's environment. Therefore, quitting smoking would result in a loss of this broad reinforcement, in addition to loss of nicotine's psychoactive effects. This broad reinforcement loss could be restored by smoking one cigarette (i.e. a lapse), helping to explain the persistence of smoking behavior. Results would provide directions for improving cessation treatments. This R21 submission fits the requirements of PA-10-069, NIH Exploratory Developmental Research Grant Program.